Prehospital transdermal glyceryl trinitrate for ultra-acute ischaemic stroke: data from the RIGHT-2 randomised sham-controlled ambulance trial.

BACKGROUND: The effect of transdermal glyceryl trinitrate (GTN, a nitrovasodilator) on clinical outcome when administered before hospital admission in suspected stroke patients is unclear. Here, we assess the safety and efficacy of GTN in the prespecified subgroup of patients who had an ischaemic stroke within the Rapid Intervention with Glyceryl trinitrate in Hypertensive stroke Trial-2 (RIGHT-2). METHODS: RIGHT-2 was an ambulance-based multicentre sham-controlled blinded-endpoint study with patients randomised within 4 hours of onset. The primary outcome was a shift in scores on the modified Rankin scale (mRS) at day 90. Secondary outcomes included death; a global analysis (Wei-Lachin test) containing Barthel Index, EuroQol-5D, mRS, telephone interview for cognitive status-modified and Zung depression scale; and neuroimaging-determined 'brain frailty' markers. Data were reported as n (%), mean (SD), median [IQR], adjusted common OR (acOR), mean difference or Mann-Whitney difference (MWD) with 95% CI. RESULTS: 597 of 1149 (52%) patients had a final diagnosis of ischaemic stroke; age 75 (12) years, premorbid mRS>2 107 (18%), Glasgow Coma Scale 14 (2) and time from onset to randomisation 67 [45, 108] min. Neuroimaging 'brain frailty' was common: median score 2 [2, 3] (range 0-3). At day 90, GTN did not influence the primary outcome (acOR for increased disability 1.15, 95% CI 0.85 to 1.54), death or global analysis (MWD 0.00, 95% CI -0.10 to 0.09). In subgroup analyses, there were non-significant interactions suggesting GTN may be associated with more death and dependency in participants randomised within 1 hour of symptom onset and in those with more severe stroke. CONCLUSIONS: In patients who had an ischaemic stroke, ultra-acute administration of transdermal GTN in the ambulance did not improve clinical outcomes in a population with more clinical and radiological frailty than seen in previous in-hospital trials.

Establishing Foundational Nonarbitrary Distinctive and Categorical Relational Responding in Children with Autism.

The present study sought to evaluate a sequence of training procedures on the emergence of foundational relational responses that underly more complex distinctive (i.e., difference) and hierarchical (i.e., categorical) relational frames. In a multiple baseline design, an initial baseline period with three children with autism showed that the participants did not select nonidentical stimuli from an array when presented the contextual cue "different." Simple discrimination training was efficacious in establishing this response and the skill transferred to a novel set of stimuli without reinforcement. In a second baseline period, participants did not demonstrate conditional identical/nonidentical relational responses when provided the contextual cues "same" and "different." Conditional discrimination training with all three participants was again efficacious in establishing the conditional reflexive and distinctive responses and the skill transferred to untrained stimuli. In a third baseline period, participants did not demonstrate correct conditional categorization/sorting. Like in the prior two training conditions, training was efficacious in establishing the target response with a generalized transfer to untrained stimuli.

Challenges and Experiences in Multicenter Prehospital Stroke Research: Narrative Data from the Rapid Intervention with Glyceryl Trinitrate in Hypertensive Stroke Trial-2 (RIGHT-2).

BACKGROUND: Ambulance services are increasingly research active and the Rapid Intervention with Glyceryl trinitrate in Hypertensive stroke Trial-2 (RIGHT-2) is the largest United Kingdom (UK) ambulance-based randomized controlled trial in stroke. We explore the complexities and challenges encountered during RIGHT-2. METHODS: Five hundred and sixteen of 1487 paramedics from eight UK ambulance services serving 54 comprehensive or primary stroke care centers screened and consented 1149 patients presenting within 4 h of FAST-positive stroke and with systolic blood pressure >120 mmHg; participants were randomized to treatment with transdermal glyceryl trinitrate versus sham patch in the ambulance. KEY FINDINGS: Working with multiple ambulance services demanded flexibility in the trial protocol to overcome variation in operating procedures to ensure deliverability. Many paramedics are novice researchers, and research concepts and practices are emerging including consent strategies in emergency stroke care. Regional variation in hospital participation and hours/days of operation presented paramedics with additional considerations prior to patient recruitment. The working hours of hospital research staff often do not reflect the 24/7 nature of ambulance work, which challenged deliverability until trial processes became fully embedded. Management of investigational medicinal product between ambulance stations, in-transit when on ambulance vehicles and on handover at hospital, necessitated an in-depth review to maintain accountability. CONCLUSION: RIGHT-2 demonstrated that although there are significant practical challenges to conducting multicenter ambulance-based research in a time-dependent environment, careful planning and management facilitated delivery. Lessons learned here will help inform the design and conduct of future ambulance-based trials.

A systematic review of ambulance service-based randomised controlled trials in stroke.

BACKGROUND: Treatment for stroke is time-dependent, and ambulance services play a vital role in the early recognition, assessment and transportation of stroke patients. Innovations which begin in ambulance services to expedite delivery of treatments for stroke are developing. However, research delivery in ambulance services is novel, developing and not fully understood. AIMS: To synthesise literature encompassing ambulance service-based randomised controlled interventions for acute stroke with consideration to the characteristics of the type of intervention, consent modality, time intervals and issues unique to research delivery in ambulance services. Online searches of MEDLINE, EMBASE, Web of Science, CENTRAL and WHO IRCTP databases and hand searches identified 15 eligible studies from 538. Articles were heterogeneous in nature and meta-analysis was partially available as 13 studies reported key time intervals, but terminology varied. Randomised interventions were evident across all points of contact with ambulance services: identification of stroke during the call for help, higher dispatch priority assigned to stroke, on-scene assessment and clinical interventions, direct referral to comprehensive stroke centres and definitive care delivery at scene. Consent methods ranged between informed patient, waiver and proxy modalities with country-specific variation. Challenges unique to the prehospital setting comprise the geographical distribution of ambulance resources, low recruitment rates, prolonged recruitment phases, management of investigational medicinal product and incomplete datasets. CONCLUSION: Research opportunities exist across all points of contact between stroke patients and ambulance services, but randomisation and consent remain novel. Early collaboration and engagement between trialists and ambulance services will alleviate some of the complexities reported. REGISTRATION NUMBER: PROSPERO 2018CRD42018075803.

Advancing drug development in pediatric oncology, a focus on cancer biology and targeted therapies: iMATRIX platform.

With the development of novel treatment therapies as well as evolving and innovative approaches to conduct clinical trials, the landscape of pediatric oncology drug development has dramatically changed in recent years. Despite this change, approvals for new drugs and labeling updates to ensure availability of proper treatment for pediatric patients with cancer remain slow. The context of drug development in pediatric tumors has also changed with regulatory initiatives in the US and Europe, creating a great need for faster development of novel drugs. Today, conventional study designs have been replaced or complemented by novel clinical trial designs, such as master protocols and platform trials, to optimize cancer drug development and enable faster regulatory approval. The iMATRIX platform is a mechanism-of-action (MOA)-based phase 1/2 trial framework for concurrently studying multiple molecules across a range of relevant pediatric tumor types, taking into account the biology of each pediatric tumor type. Six studies have been conducted, ongoing, or planned on the iMATRIX platform - investigating atezolizumab, cobimetinib, entrectinib, idasanutlin, alectinib, and glofitamab. A brief overview of study designs and characteristics are shared in this article, along with learnings from them.

Toward a Holistic Understanding and Models of Nonphotochemical Quenching Effects on In Vivo Fluorometry of Chlorophyll a in Coastal Waters.

Nonphotochemical quenching (NPQ) is known to depress in vivo fluorescence (IVF) of chlorophyll a (Chla) in aquatic environments, which makes it difficult to interpret the hour-to-hour variations in Chla measured by in situ fluorometers. We hypothesized that ratios between quenched and unquenched IVF are a function of both NPQ and photochemical quenching. In this study, two diatom model species Thalassiosira pseudonana (CCMP1335) and Thalassiosira weissflogii (CCMP1047) incubated under a sinusoidal light:dark cycle were studied; IVF was recorded continuously, and Chla and photo-physiological variables were measured seven times a day. The maximal decline in Chla-specific IVF (IVFB ) attributable to quenching was 50% under the experimental settings. An NPQ and photochemical quenching-based modeling equation exhibited a better match to the measured IVFB than equations representing the sole NPQ effect. Photochemical quenching induced by measuring light beam varied substantially during the day, and the part of the model for this process is excitation intensity-dependent (which is differed between models of in situ fluorometers, implying no straightforward method to correct Chla for all instrument models, instrument-specific parameterization is required). The forms of the IVFB -light relationship are discussed as well. The findings foster a holistic understanding of NPQ effects on in vivo Chla fluorometry.

Glofitamab for Relapsed or Refractory Diffuse Large B-Cell Lymphoma.

BACKGROUND: The prognosis for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) is poor. Glofitamab is a bispecific antibody that recruits T cells to tumor cells. METHODS: In the phase 2 part of a phase 1-2 study, we enrolled patients with relapsed or refractory DLBCL who had received at least two lines of therapy previously. Patients received pretreatment with obinutuzumab to mitigate cytokine release syndrome, followed by fixed-duration glofitamab monotherapy (12 cycles total). The primary end point was complete response according to assessment by an independent review committee. Key secondary end points included duration of response, survival, and safety. RESULTS: Of the 155 patients who were enrolled, 154 received at least one dose of any study treatment (obinutuzumab or glofitamab). At a median follow-up of 12.6 months, 39% (95% confidence interval [CI], 32 to 48) of the patients had a complete response according to independent review. Results were consistent among the 52 patients who had previously received chimeric antigen receptor T-cell therapy (35% of whom had a complete response). The median time to a complete response was 42 days (95% CI, 42 to 44). The majority (78%) of complete responses were ongoing at 12 months. The 12-month progression-free survival was 37% (95% CI, 28 to 46). Discontinuation of glofitamab due to adverse events occurred in 9% of the patients. The most common adverse event was cytokine release syndrome (in 63% of the patients). Adverse events of grade 3 or higher occurred in 62% of the patients, with grade 3 or higher cytokine release syndrome in 4% and grade 3 or higher neurologic events in 3%. CONCLUSIONS: Glofitamab therapy was effective for DLBCL. More than half the patients had an adverse event of grade 3 or 4. (Funded by F. Hoffmann-La Roche; ClinicalTrials.gov number, NCT03075696.).

Top-Down Attentional Processing and Relational Density Evident in Word Search Performance of Children.

Relational frame theory and extensions (e.g., relational density theory; Belisle & Dixon, 2020a, 2020b) provides a behavioral model for top-down attentional processing, where attention is oriented in terms of arbitrarily applicable verbal relations through the transformation of stimulus function. Children's games may provide a strategy for testing transformations of stimulus function when developing new language skills, such as when working with children with autism. Three children with autism underwent relational training to establish lean and dense arbitrary classes. Prior-to relational training, participants were more likely to locate familiar words over unfamiliar words within a word-search task. Following relational training, participants were more likely to locate words that participated in high-density relational classes over neutral or low-density relational classes. These results support the use of common games to supplement relational training with children with autism and provide evidence that top-down attentional processing may involve transformations of stimulus function and can be predicted and influenced through relational training to establish high-density relational classes.

Time intervals and distances travelled for prehospital ambulance stroke care: data from the randomised-controlled ambulance-based Rapid Intervention with Glyceryl trinitrate in Hypertensive stroke Trial-2 (RIGHT-2).

OBJECTIVES: Ambulances offer the first opportunity to evaluate hyperacute stroke treatments. In this study, we investigated the conduct of a hyperacute stroke study in the ambulance-based setting with a particular focus on timings and logistics of trial delivery. DESIGN: Multicentre prospective, single-blind, parallel group randomised controlled trial. SETTING: Eight National Health Service ambulance services in England and Wales; 54 acute stroke centres. PARTICIPANTS: Paramedics enrolled 1149 patients assessed as likely to have a stroke, with Face, Arm, Speech and Time score (2 or 3), within 4 hours of symptom onset and systolic blood pressure >120 mm Hg. INTERVENTIONS: Paramedics administered randomly assigned active transdermal glyceryl trinitrate or sham. PRIMARY AND SECONDARY OUTCOMES: Modified Rankin scale at day 90. This paper focuses on response time intervals, distances travelled and baseline characteristics of patients, compared between ambulance services. RESULTS: Paramedics enrolled 1149 patients between September 2015 and May 2018. FINAL DIAGNOSIS: intracerebral haemorrhage 13%, ischaemic stroke 52%, transient ischaemic attack 9% and mimic 26%. Timings (min) were (median (25-75 centile)): onset to emergency call 19 (5-64); onset to randomisation 71 (45-116); total time at scene 33 (26-46); depart scene to hospital 15 (10-23); randomisation to hospital 24 (16-34) and onset to hospital 97 (71-141). Ambulances travelled (km) 10 (4-19) from scene to hospital. Timings and distances differed between ambulance service, for example, onset to randomisation (fastest 53 min, slowest 77 min; p<0.001), distance from scene to hospital (least 4 km, most 20 km; p<0.001). CONCLUSION: We completed a large prehospital stroke trial involving a simple-to-administer intervention across multiple ambulance services. The time from onset to randomisation and modest distances travelled support the applicability of future large-scale paramedic-delivered ambulance-based stroke trials in urban and rural locations. TRIAL REGISTRATION NUMBER: ISRCTN26986053.

Motivational Interviewing and Self-Determination Theory in Suicide Assessment: A Practical Application to Aid Residents' Management of Suicide.

Suicide is a problem on the rise in the United States. One significant avenue to help reverse the trend is through family medicine and interventions within primary care clinics. This can be a significant stressor for many family medicine physicians to manage patients experiencing suicidal ideation within their busy schedule. Motivational Interviewing is an evidence-based method of interacting with patients in a healthy and collaborative manner. The literature is growing on how to use Motivational Interviewing in assessments of suicidal ideation. Additionally, Self-Determination Theory proposes that individuals have three basic needs: a sense of connection, a level of autonomy, and a degree of competence. These needs and the associated principles of intrinsic and extrinsic motivation help to explain why Motivational Interviewing can be so helpful in the change process. By examining the principles of Motivational Interviewing and Self-Determination Theory residents will be able to better create an environment conducive to collaborative sharing, honest discussion, and meaningful assessment to ensure safety for patients in primary care.

Cognitive-behavioral therapy for insomnia for primary care: Review of components and application for residents in primary care.

Healthy sleep patterns are a significant component of good physical and mental health. Quality sleep can be affected by such things as stress, age, pregnancy, physical health problems, and shift work. Behaviors related to sleep problems can be one of three types: predisposing, precipitating, and perpetuating. Additionally, cognitive processes related to sleep quality tend to be predominated by sleep thinking or insomnia thinking. Multiple medical organizations promote Cognitive Behavioral Therapy for Insomnia as a best practice for clinical management of sleep problems and disorders. Cognitive Behavioral Therapy for Insomnia consists of five components aimed at addressing both the behavioral and cognitive impediments to high quality sleep. These components are sleep hygiene, relaxation, sleep restriction, stimulus control, and cognitive therapy. This paper will address each component, as well as provide a patient education pattern well suited for primary care settings.

Design and Evaluation of Interprofessional Training Program for Healthcare Students from Collectivistic Culture.

Background: Healthcare is team-based, and with increased mobility of healthcare workers, most of them will work with team members from all over the globe. Interprofessional education (IPE) research has mostly focused on specially designed programs in academic health institutions to prepare students for multidisciplinary work. Few IPE programs aim to integrate students with mixed disciplines from collectivist cultures. Methods: This mixed-methods study was conducted between June and August 2019. Surveys and an e-portfolio were recorded of 33 final-year and graduated health professional students' participation in an 8-week IPE summer program at a medical school in Ireland. Survey results are described, and the content of portfolios was analyzed based on the deductive analysis of qualitative data derived from questions. Results: Students reported the greatest improvement in presentation skills (63.6%), followed by communication (54.5%), team working skills (93.9%), and interprofessional learning (42.4%), respectively. Qualitative findings highlighted challenges for students from a collectivist culture adapting to an IPE: uncomfortable verbally expressing themselves in problem-based learning (PBL) and how to work with other sex. Positive themes about IPE that emerged were enjoyment in sharing ideas and building trust with PBL groups. We learned that the program had to be flexible enough to meet the educational requirements of a target community with mixed English language ability and adaptability to IPE. Conclusion: The authors propose that an international PBL-based summer program is effective in improving healthcare students' attitudes towards IPE. This study provides valuable insights to facilitate the development of further IPE programs to increased collaboration between students across various healthcare disciplines. Supplementary Information: The online version contains supplementary material available at 10.1007/s40670-022-01536-7.

An Examination of the Intervention-Enhancing Effect of Acceptance and Commitment Therapy-Based Training on Direct Service Professionals' Performance in the Workplace.

Direct service professionals (DSPs) provide treatment to individuals with developmental disabilities; however, high levels of performance are not always prevalent among these professionals. The present study examined the effect of an intervention package with verbal and written performance feedback and a performance-based lottery alone as part of a treatment package including an acceptance and commitment therapy (ACT)-based training program on the frequency and technical competence of active treatment for individuals with disabilities provided by DSPs. Both intervention groups performed significantly better than the control group on all observational measures (p < .05). The performance enhancement intervention (PEI) plus ACT group outperformed the PEI group significantly in frequency of active treatment at posttest (p < .05). Self-reported levels of psychological flexibility, workplace stress, and job satisfaction remained stable for all three groups from pre- to posttest despite the increased performance among DSPs in the two intervention groups.

Relational Behavior and ACT: A Dynamic Relationship.

Acceptance and commitment therapy (ACT) and its counterpart, relational frame theory (RFT), represent emerging areas of research and professional interest for behavior analysts. We extend traditional RFT approaches by emphasizing relational framing as a dynamic pattern of behavior with implications for ACT-based strategies implemented by behavior analysts in practice and in research. We borrow from emerging approaches within affective dynamics, relational density theory, and the hyper-dimensional multilevel model to develop some immediate considerations for practitioners. We then extend an approach grounded in relational dynamics to the six core processes of the ACT hexaflex not only to influence negative affective patterns of relational behavior but also to promote greater psychological flexibility and well-being. Finally, we turn this account inward to discuss our own rigidity as a field and the necessity to engage more flexibly with our own science, ultimately to improve the lives of clients whom we serve.

A Large-Scale Naturalistic Evaluation of the AIM Curriculum in a Public-School Setting.

This study evaluated the effectiveness of the AIM curriculum when implemented in a public-school setting by schoolteachers and direct care staff. Three hundred eighteen students took part in this quasiexperimental design where all received the AIM curriculum every day for an entire school year. The participants completed a series of self-assessments (the Avoidance and Fusion Questionnaire for Youth, the Child and Adolescent Mindfulness Measure, and the Strength and Difficulties Questionnaire) at the onset of the study and at the end of the school year to assess psychological flexibility, mindfulness, and emotional behavioral skills. Results suggest that at the end of the school year, participants increased psychological flexibility and mindfulness. State standardized testing scores also showed increases school-wide as compared to the previous 2 years. These results suggest that the AIM curriculum may be effective in large school settings, appeared easy to implement by school staff to address the needs of both the individual student and the entire student body, and likely participated in improving school-wide academic success.

Using Relational Training to Improve Performance During Acceptance and Commitment Training Sessions.

The current study investigated the effect of relational training on improving engagement during acceptance and commitment training (ACT) sessions that aimed to reduce maladaptive behavior. Three female children diagnosed with autism participated in the current research. The relational training protocol involved eight programs designed to improve participants' ability to engage in relational responding. A concurrent multiple-baseline across-participants design was used, and participants' maladaptive behavior during ACT sessions was recorded. Results indicated a decrease in maladaptive behavior for one of the three participants, with a medium to large treatment effect. A secondary measure also showed improvement in all three participants' performance during ACT sessions. The percentage of nonoverlapping data and Cohen's d suggest a small to moderate treatment effect. Implications for implementing ACT with individuals diagnosed with autism are discussed.

Utilizing the AIM Curriculum to Improve Job Performance in an Educational Setting for Children With Autism and Related Disabilities.

The current study evaluated the effect of brief, daily present moment awareness activities on the work performance of paraprofessionals working at a school for children with disabilities. A nonconcurrent multiple-baseline design across three participants evaluated changes in staff-initiated interactions with students and staff's accuracy of data collection on student behavior. Relative to baseline, participants demonstrated an average increase in staff-initiated interactions and an increase in the average percentage accuracy of data collection. Participants averaged 10.02 (range 3.4-16.67) staff-initiated interactions during baseline and 15.38 (range 9.75-24.4) during the intervention phase. Relative to baseline, two of the three participants demonstrated an increase in their average accuracy of data collection on student behavior. Participants' average data collection accuracy was 56.9% (range 40%-86.67%) during baseline and 91.98% (range 86.41%-100%) during intervention. The average percentage of nonoverlapping data was 61.67% (range 25%-100%) for staff-initiated interactions and 33.33% (range 0%-100%) for data collection accuracy. Implications and possibilities for future research related to acceptance and commitment training interventions in workplace environments are discussed.

Correction to: A Large-Scale Naturalistic Evaluation of the AIM Curriculum in a Public-School Setting.

[This corrects the article DOI: 10.1007/s40617-021-00569-5.].

Pre-hospital transdermal glyceryl trinitrate in patients with stroke mimics: data from the RIGHT-2 randomised-controlled ambulance trial.

BACKGROUND: Prehospital stroke trials will inevitably recruit patients with non-stroke conditions, so called stroke mimics. We undertook a pre-specified analysis to determine outcomes in patients with mimics in the second Rapid Intervention with Glyceryl trinitrate in Hypertensive stroke Trial (RIGHT-2). METHODS: RIGHT-2 was a prospective, multicentre, paramedic-delivered, ambulance-based, sham-controlled, participant-and outcome-blinded, randomised-controlled trial of transdermal glyceryl trinitrate (GTN) in adults with ultra-acute presumed stroke in the UK. Final diagnosis (intracerebral haemorrhage, ischaemic stroke, transient ischaemic attack, mimic) was determined by the hospital investigator. This pre-specified subgroup analysis assessed the safety and efficacy of transdermal GTN (5 mg daily for 4 days) versus sham patch among stroke mimic patients. The primary outcome was the 7-level modified Rankin Scale (mRS) at 90 days. RESULTS: Among 1149 participants in RIGHT-2, 297 (26%) had a final diagnosis of mimic (GTN 134, sham 163). The mimic group were younger, mean age 67 (SD: 18) vs 75 (SD: 13) years, had a longer interval from symptom onset to randomisation, median 75 [95% CI: 47,126] vs 70 [95% CI:45,108] minutes, less atrial fibrillation and a lower systolic blood pressure and Face-Arm-Speech-Time tool score than the stroke group. The three most common mimic diagnoses were seizure (17%), migraine or primary headache disorder (17%) and functional disorders (14%). At 90 days, the GTN group had a better mRS score as compared to the sham group (adjusted common odds ratio 0.54; 95% confidence intervals 0.34, 0.85; p = 0.008), a difference that persisted at 365 days. There was no difference in the proportion of patients who died in hospital, were discharged to a residential care facility, or suffered a serious adverse event. CONCLUSIONS: One-quarter of patients suspected by paramedics to have an ultra-acute stroke were subsequently diagnosed with a non-stroke condition. GTN was associated with unexplained improved functional outcome observed at 90 days and one year, a finding that may represent an undetected baseline imbalance, chance, or real efficacy. GTN was not associated with harm. TRIAL REGISTRATION: This trial is registered with International Standard Randomised Controlled Trials Number ISRCTN 26986053 .